A hypothesis consistent with the known facts is that endotoxin appearing in the circulating plasma by direct leakage from the gut or derived from endotoxin producing bacteria translocated from the gut in response to injury is the trigger for the abnormalities of cellular immunity noted after major burns or serious injury. We propose to test this hypothesis by studying patients who have sustained major burns or traumatic injury and a mouse model of burn injury in order to correlate serum endotoxin levels with cytokine production by adherent cells, lymphocytes and PMN and with cytokine messenger RNA expression by the same cells. We will also correlate adherent cell PGE2 production with lymphocyte activation and cytokine production. We will investigate inhibitors of the arachadonic acid pathway on the expression of messenger RNA for IL-2 and interferon gamma. We will also investigate second messenger activity in lymphocytes by measuring by cyclic AMP levels and will investigate the mechanism of increased sensitivity of lymphocytes to PGE2 after injury by exposing normal lymphocytes to cytokines, cortisol and PGE2. Finally we will utilize the animal model of burn injury to determine whether immunoregulatory regimens which increase survival after septic challenge will increase splenocyte IL-2 production and/or diminish splenocyte proinflammatory cytokine production.